PROJECT SUMMARY The immune response is strongly implicated in the pathogenesis of multiple neurodegenerative disorders, including Alzheimer's disease (AD), dementia in Down Syndrome (DS), and traumatic brain injury (TBI)/chronic traumatic encephalopathy (CTE) in professional fighters (PF). These disorders have some degree of amyloid (A?) and tau pathology in common, but the level of AD-related progression varies between these groups. TREM2 (triggering receptor expressed on myeloid cells 2) is a risk factor for AD. In an AD mouse model, disease progression-dependent effects have been linked to TREM2 deficiency. TREM2 is reportedly elevated in young DS. Furthermore, in a TBI mouse model, TREM2 deficiency altered acute macrophage distribution and improved recovery later. This evidence suggests TREM2 plays a role in the progressive immune response in AD, TBI and DS. Epigenetic factors have been described as regulators of TREM2 expression. However, despite implications in mouse models, there are critical unknowns about how TREM2 influences the progressive immune response in human AD, TBI and DS. Our group has discovered a relationship between peripheral sTREM2 and c-reactive protein in early AD, 8 and CCL2 (and other immune factors) in late AD, 8 as well as epigenetic factors in early and late AD. Given our recent discoveries, the overall objective is to demonstrate that epigenetic regulation of peripheral TREM2 sustains elevated TREM2 in some individuals and in turn influences a specific progressive immune phenotype. We believe that methylation and miRNA act in concert to dynamically regulate TREM2 which in turn has downstream effects on the progressive immune response. Therefore, in a longitudinal cohort of AD, DS and PF, we will test the hypothesis that dynamic epigenetic regulation of peripheral TREM2 underlies the neurodegenerative immune response and thus contributes to variability in AD-related progression. First, it will be demonstrated that specific phenotypes (elevated TREM2, sTREM2 and immune factors) are significantly different in AD risk individuals in a cohort of AD, DS and PF. Second, it will be demonstrated that there is a sustained TREM2 epigenetic (increased TREM2 methylation and decreased miR-425-5p) relationship with immune factor phenotype in a longitudinal cohort of AD, DS and PF. Third, we will demonstrate that targeting TREM2 epigenetics modifies TREM2 expression and in turn influences immune factor phenotype in vitro in a similar manner as observed in vivo. The proposed research plan will provide critical missing information about whether peripheral TREM2 epigenetics influences the immune response in vitro and in vivo in humans and has shared AD-related progression dependent effects in these neurodegenerative disorders. This novel information will demonstrate that epigenetic regulation of TREM2 is a feasible immune-related therapeutic target for early intervention in neurodegenerative disorder progression.